Mifepristone modulates response to CDK4/6 inhibition in progesterone receptor isoform A-high breast cancer models
Abstract
CDK4/6 inhibitors have significantly improved outcomes in estrogen receptor–positive breast cancer. Mifepristone, a progesterone receptor (PR) antagonist, is under investigation in tumors with high levels of PR isoform A (PRA). Here, we evaluated the therapeutic potential of combining mifepristone with CDK4/6 inhibitors. Mifepristone enhanced CDK4/6 inhibitor efficacy in PRA-expressing T47D and T47D-YA cells, whereas it increased proliferation in PR isoform B-overexpressing T47D-YB cells; however, palbociclib retained antiproliferative activity. The combination reduced proliferation through RB dephosphorylation and E2F1 downregulation. ChIP–qPCR and transient transfection assays suggested a direct effect of mifepristone on E2F1 transcription. Ex vivo treatment of breast cancer tissue slices from two of three tumors with high PRA levels showed optimal inhibition with the combination, while complete inhibition was observed with all treatments in the third tumor. Consistent effects were obtained in T47D xenografts in vivo. In murine PR+ mammary carcinomas, sensitivity to palbociclib was independent of responsiveness to mifepristone. Palbociclib sensitivity correlated with elevated CDKN2C expression, whereas resistance was associated with increased NOTCH1 expression. Importantly, pharmacologic Notch inhibition restored palbociclib sensitivity in resistant cells. These findings suggest that mifepristone may potentiate CDK4/6 inhibition in PRA-high breast cancers and identify the Notch pathway as a mediator of intrinsic palbociclib resistance.
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BibTeX
@article{pataccini2026mifepristone,
title = {{Mifepristone modulates response to CDK4/6 inhibition in progesterone receptor isoform A-high breast cancer models}},
author = {Gabriela Pataccini and Andrés Elia and Luisa Ambrosio and Leo Saldain and Paola Rojas and Silvia I. Vanzulli and Karin Villar and Javier Burruchaga and Florencia Torres and Paula Martínez-Vázquez and Carol A. Sartorius and Caroline A. Lamb and Victoria Fabris and Virginia Novaro and Martín C. Abba and Sebastián Giulianelli and Claudia Lanari},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-72087-9},
url = {https://www.nature.com/articles/s41598-026-72087-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mifepristone modulates response to CDK4/6 inhibition in progesterone receptor isoform A-high breast cancer models
AU - Gabriela Pataccini
AU - Andrés Elia
AU - Luisa Ambrosio
AU - Leo Saldain
AU - Paola Rojas
AU - Silvia I. Vanzulli
AU - Karin Villar
AU - Javier Burruchaga
AU - Florencia Torres
AU - Paula Martínez-Vázquez
AU - Carol A. Sartorius
AU - Caroline A. Lamb
AU - Victoria Fabris
AU - Virginia Novaro
AU - Martín C. Abba
AU - Sebastián Giulianelli
AU - Claudia Lanari
PY - 2026
DA - 2026/10/14
JO - Scientific Reports
DO - 10.1038/s41598-026-72087-9
UR - https://www.nature.com/articles/s41598-026-72087-9
AB - CDK4/6 inhibitors have significantly improved outcomes in estrogen receptor–positive breast cancer. Mifepristone, a progesterone receptor (PR) antagonist, is under investigation in tumors with high levels of PR isoform A (PRA). Here, we evaluated the therapeutic potential of combining mifepristone with CDK4/6 inhibitors. Mifepristone enhanced CDK4/6 inhibitor efficacy in PRA-expressing T47D and T47D-YA cells, whereas it increased proliferation in PR isoform B-overexpressing T47D-YB cells; however, palbociclib retained antiproliferative activity. The combination reduced proliferation through RB dephosphorylation and E2F1 downregulation. ChIP–qPCR and transient transfection assays suggested a direct effect of mifepristone on E2F1 transcription. Ex vivo treatment of breast cancer tissue slices from two of three tumors with high PRA levels showed optimal inhibition with the combination, while complete inhibition was observed with all treatments in the third tumor. Consistent effects were obtained in T47D xenografts in vivo. In murine PR+ mammary carcinomas, sensitivity to palbociclib was independent of responsiveness to mifepristone. Palbociclib sensitivity correlated with elevated CDKN2C expression, whereas resistance was associated with increased NOTCH1 expression. Importantly, pharmacologic Notch inhibition restored palbociclib sensitivity in resistant cells. These findings suggest that mifepristone may potentiate CDK4/6 inhibition in PRA-high breast cancers and identify the Notch pathway as a mediator of intrinsic palbociclib resistance.
SN - 2045-2322
ER -